Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Measles seroprevalence in human immunodeficiency virus-infected adults born in the era of measles vaccination.

OBJECTIVE: Widespread use of the measles vaccine should lead to the elimination of this disease. Here, we study the seroprevalence of measles in a cohort of adults living with HIV born after the introduction of measles vaccine in France and attempt to identify risk factors for the absence of serum measles antibody. DESIGN: In this multi-centre cross-sectional study, adult outpatients born after 1980 were screened for the presence of measles IgG antibody. Demographic and clinical data were obtained from the standardized electronic medical record system. Univariate and multivariate logistic regressions were performed to identify factors associated with the absence of measles antibodies. RESULTS: Between April 2019 and April 2020, 648 participants were enrolled. The median age was 33 years, 53.6% were born outside of France, and 74% were considered as socially deprived. Plasma HIV RNA was undetectable in 86% of patients. Among 603 evaluable patients, measles serology was positive in 87.2%. Only 81.8% of the patients with documented vaccination tested positive for measles IgG. Younger age was significantly associated with the absence of measles serum antibodies ( P  = 0.004 for each 10-year lower), as was birth in France ( P  < 0.001) and absence of social vulnerability ( P  = 0.04). CONCLUSION: The current study revealed a low seroprevalence of measles compared with that previously reported in France 6 years earlier and to the expected rate to achieve herd immunity. Checking vaccination record should be systematically carried out in patients living with HIV to fill the immunity gaps.

Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy.

OBJECTIVES: Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes. METHODS: In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery. RESULTS: Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment,  P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir. CONCLUSION: We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.

Metabolic risk factors in young adults infected with HIV since childhood compared with the general population.

AIM: Metabolic risk factors are poorly documented for the first generation of young adults who have lived with HIV since childhood. We compared their metabolic profile with that of adults of same age from the general population. METHODS: We conducted a cross-sectional analysis of data from two populations: (1) COVERTE (ANRS-CO19), a French national cohort of 18 to 30-year-old patients HIV-infected since childhood, and (2) ENNS, a national cross-sectional population-based household survey on nutrition. Body mass index (BMI), blood pressure, waist circumference, fasting glucose, triglycerides, and HDL-, LDL- and total cholesterol were measured in both studies. Direct standardization on overweight and education level and logistic regression were used to compare the prevalence of metabolic abnormalities between the two populations. RESULTS: Data from 268 patients from COVERTE and 245 subjects from ENNS were analyzed. Tobacco use was similar in both groups. HIV-infected patients had increased mean waist-to-hip ratio and triglycerides to HDL-cholesterol ratio and decreased mean HDL-cholesterol as compared to their counterparts from the general population in both genders. In HIV-infected patients, metabolic syndrome was identified in 13.2% of men (95% confidence interval [CI]: 7.1-19.2) and 10.4% (95% CI: 5.4-15.3) of women versus 10.6% (95%CI: 1.5-19.7) and 1.7% (95%CI: 0-4.1) in subjects from the general population, respectively. CONCLUSION: Young adults infected with HIV since childhood had a higher prevalence of dyslipidemia and metabolically detrimental fat distribution than adults of same age of the general population, supporting close monitoring for cardiometabolic diseases.

T-Cell Receptor Excision Circles in HIV-Exposed, Uninfected Newborns Measured During a National Newborn Screening Program for Severe Combined Immunodeficiency.

Severe combined immunodeficiency screening by measuring T-receptor excision circles at birth allows evaluation of the impact of various maternal conditions on newborn immunity. The slight decrease observed in a French cohort of newborns to HIV-infected mothers can be explained by the confounding factors of prematurity and African descent.

Developmental delay and behavioral disorders in 59 HIV-exposed uninfected infants.

BACKGROUND: Antiretroviral therapy (ART) in HIV pregnant women has led to a dramatic decrease in the rate of HIV mother-to-child transmission but this benefit is counterbalanced with adverse effects related to in utero and neonatal exposure to ART. In 2013, some parents described neurodevelopmental disorders in their children. METHODS: A standardized letter was sent to the 133 women who delivered in Nantes hospital from 01/01/2003 to 31/12/2012 (167 births). RESULTS: Response rate was 33%. Over a 10-year period, 7 children had behavioral disorders and/or cognitive/developmental delay, 1 child had developmental delay + growth retardation and 2 experienced cancer. CONCLUSIONS: We found a significant association between neurodevelopmental disorders, preterm birth and exposure to 3 nucleoside reverse transcriptase inhibitors (NRTIs). Further studies are needed and long-term follow-up into adulthood should continue.

Risk of cancer in children exposed to didanosine in utero.

BACKGROUND: Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine. METHODS: Updated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population. RESULTS: A total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)]. CONCLUSION: There are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.

Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.

OBJECTIVES: The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1. PATIENTS AND METHODS: This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration. RESULTS: The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011). CONCLUSIONS: The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.

No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception.

BACKGROUND: The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT. METHODS: A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation. RESULTS: The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2). CONCLUSIONS: Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

The spectrum of HIV mother-to-child transmission risk.

INTRODUCTION: With the implementation of combined antiretroviral therapy (cART) and prevention of mother-to-child transmission (MTCT) we observed dramatic decreases in rates of perinatal MTCT of HIV, 0.3% in France in women with plasma viral load (pVL) <50 c/mL at delivery. We describe a case of MTCT which occurred despite virologic suppression of the mother at delivery, the first case in our centre since 2002. DESCRIPTION OF THE CASE: A 26-year-old black woman, Guinea-native, living in France since 2007, was diagnosed with HIV-1 CRF02 in 2008 and lost to follow-up since November 2012 after second delivery (2 female born in March 2009 and October 2012, uninfected). Third pregnancy began in July 2013 and baseline characteristics in September were as follows: week 13 of gestational age (GA), CDC stage A, CD4 317/mm(3), pVL 4.89 log c/mL. cART with abacavir/lamivudine and atazanavir/ritonavir 300/100 mg daily (qd) was introduced. VL decreased to 2.4 log c/mL in 4 weeks and CD4 increased to 456/mm(3). In December, at week 22 of GA, viral rebound at 4.14 log c/mL due to sub-optimal maternal adherence was observed. After counselling, pVL decreased to 1.69 log c/mL in March 2014, at week 35 of GA and 1.3 log c/mL at delivery. As pVL was <400 c/mL at week 36 of GA, vaginal delivery with IV zidovudine was decided. However, because of poor/uncertain maternal adherence to cART, the neonate was treated with a combination of 2 drugs (lamivudine-nevirapine) with the 4-week zidovudine regimen, until the result of delivery pVL. This combination was stopped at day 2 when maternal delivery pVL (22 c/mL) was received and standard oral zidovudine prophylaxis was continued. Infant was tested for HIV infection at baseline (day 3) and found to be HIV-infected (HIV-RNA 60 c/mL) attesting in-utero HIV transmission. On day 15, zidovudine prophylaxis was discontinued and treatment for HIV infection initiated with standard cART according to the French Paediatric Antiretroviral Guidelines. CONCLUSIONS: The risk of HIV acquisition is low in infants born to women who receive standard cART during pregnancy and labour and achieve undetectable VL at delivery. However, transmission remains a hazard, with possibility of in-utero infection during episodes of non-adherence, and the risk of a possible MTCT has to be mentioned to all pregnant women.

Prevalence and risk factors of sleep disturbances in a large HIV-infected adult population.

INTRODUCTION: Sleep disturbances are frequently reported in HIV-infected patients but there is a lack of large studies on prevalence and risk factors, particularly in the context of current improved immuno-clinical status and use of the newest antiretrovirals (ARV). METHOD: Cross-sectional study to evaluate the prevalence and factors associated with sleep disturbance in adult HIV-infected patients in six French centres of the region "Pays de la Loire". Patients filled a self-administered questionnaire on their health behaviour, sleep attitudes (Pittsburgh Sleep Quality Index PSQI), quality of life (WHO QOL HIV BREF questionnaire) and depression (Beck depression Inventory (BDI)-II questionnaire). Socio-demographic and immunovirologic data, medical history, ARVs were collected. RESULTS: From November 2012 to May 2013, 1354 consecutive non-selected patients were enrolled. Patients' characteristics were: 73.5% male, median age 47 years, active employment 56.7%, France-native 83% and Africa-native 14.7%, CDC stage C 21%, hepatitis co-infection 13%, lipodystrophy 11.8%, dyslipidemia 20%, high BP 15.1%, diabetes 3%, tobacco smokers 39%, marijuana and cocaine users, 11.7% and 1.7% respectively, and excessive alcohol drinkers 9%. Median (med) duration of HIV infection was 12.4 years, med CD4 count was 604/mm(3); 94% of Patients were on ARVs, 87% had undetectable viral load. Median sleeping time was 7 hours. Sleep disturbances (defined as PSQI score >5) were observed in 47% of the patients, more frequently in female (56.4%) than in male (43.9%) (p<0.05) and moderate to serious depressive symptoms (BDI score>19) in 19.7% of the patients. In multivariate analysis, factors associated with sleep disturbances (p<0.05) were depression (odds ratio [OR] 4.6; 95% confidence interval [CI] 3.2-6.8), male gender (OR 0.7; CI 0.5-0.9), active employment (OR 0.7; CI 0.5-0.9), living single (OR 1.5; CI 1.2-2.0), tobacco-smoking (OR 1.3; CI 1.0-1.8), duration of HIV infection (>10 vs. <10 y.) (OR 1.5; CI 1.1-2.0), ARV regimen containing nevirapine (OR 0.7; CI 0.5-0.9) or efavirenz (OR 0.5; CI 0.3-0.7). CONCLUSIONS: Prevalence of sleep disturbances is high in this HIV population and roughly similar to the French population. Associated factors are rather related to social and psychological status than HIV infection. Depression is frequent and should be taken in care to improve sleep quality.

Nevirapine-raltegravir combination, an NRTI and PI/r sparing regimen, as maintenance antiretroviral therapy in virologically suppressed HIV-1-infected patients.

BACKGROUND: Nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)/ritonavir sparing regimens may be useful to some HIV-infected patients. Nevirapine (NVP) and raltegravir (RAL) are both potent antiretrovirals with good long-term safety profiles. METHODS: We retrospectively identified from our electronic database all patients with HIV RNA<50 copies/ml for >6 months on an NVP-containing regimen and no prior exposure to integrase strand transfer inhibitors who were switched to RAL plus NVP. Data was collected for 36 months or until discontinuation of RAL plus NVP for any reason. RESULTS: A total of 39 patients (30 male) were included in this analysis. Median duration of prior antiretroviral therapy was 14 years (IQR 10-17) and median duration with plasma HIV-1 RNA<50 copies/ml prior to switch was 50 months (IQR 22-96). Switched regimens included mainly a boosted PI (n=24) or tenofovir disoproxil fumarate/emtricitabine (n=12). After switching, the percentages of patients with HIV-1 RNA<50 copies/ml were 87.2% (95% CI 76.7, 97.7) and 82.1% (95% CI 70.0, 94.1) at 6 and 12 months, respectively, in the intent-to-treat-exposed analysis, 97.1% (95% CI 91.6, 100) and 94.1% (95% CI 86.2, 100), respectively, in the per-protocol analysis. All patients with follow-up to month 24 (n=22) or month 36 (n=14) had HIV-1 RNA<50 copies/ml. One virological failure was observed (related to archived non-nucleoside reverse transcriptase inhibitor resistance mutation). During follow-up, no patient experienced Grade 3 or 4 adverse events. Median values of serum creatinine and lipids significantly improved after switch. CONCLUSIONS: In patients with prolonged HIV-1 RNA<50 copies/ml, switching to NVP-RAL combination maintained virological suppression throughout 36 months. This combination deserves further evaluation in patients unable to tolerate NRTI or PI/ritonavir agents.

Evaluation of residual viremia and quantitation of soluble CD14 in a large cohort of HIV-infected adults on a long-term non-nucleoside reverse transcriptase inhibitor-based regimen.

Beyond virological suppression and immunologic recovery, the objective of long-term antiretroviral therapy is to suppress maximally viremia and to control for persistent immune activation. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens are associated with lower residual viremia. The objective of the study was to evaluate the impact of long term NNRTI-containing treatment on residual viremia and on monocyte activation in a cohort of patients infected with HIV-1. To identify factors associated with residual viremia, adult patients infected with HIV on nevirapine or efavirenz-based therapy with viral load <50 copies/ml for >6 months were included. Residual plasma viremia was quantified using an adapted Cobas/Taqman HIV-1 assay. Viral loads with no detected signal were considered as <1 copy/ml. Monocyte activation was evaluated by quantitation of plasma sCD14 by ELISA assay at the time of residual viremia measurement. Logistic regression was used to determine factors associated with residual viremia <1 copy/ml. In this cohort of 421 patients on long-term NNRTI regimen, three quarters had a residual viremia <1 copy/ml. In multivariate analysis, duration of plasma viral load below 50 copies/ml was the only factor associated with residual viremia <1 copy/ml. Soluble CD14 was in the normal range although treatment with nevirapine was associated with a significant lower level of sCD14 compared to efavirenz. Residual viremia <1 copy/ml was frequent in this cohort of patients with long term virological control and confirmed the results of previous studies. Apart from its antiviral effect, nevirapine as well as efavirenz could decrease monocyte activation.

Virological response to darunavir in patients infected with HIV is linked to darunavir resistance-associated mutations corrected by the count of mutations with positive impact and is not associated with pharmacological and combined virological/pharmacological parameters.

The relationships between virological (darunavir resistance-associated mutations), pharmacological (darunavir trough plasma concentration), combined virological/pharmacological [darunavir genotypic inhibitory quotient (GIQ)] parameters and virological response were evaluated in experienced patients infected with human immunodeficiency virus. In this retrospective study (48 patients), the relationship between these parameters and the virological response was investigated by multivariate logistic regression. Darunavir GIQ is defined as the ratio between darunavir trough plasma concentration and the count of darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V) corrected or not corrected by the count of mutations with positive impact (V82A and E35D). The pharmacological and combined virological/pharmacological parameters failed to predict virological response. The count of darunavir resistance-associated mutations corrected by the count of V82A and E35D mutations was the single parameter significantly (P = 0.027) associated with virological response. This result suggests that both negative and positive impacts of mutations including V82A and E35D should be considered to predict virological response in experienced patients.

Four year follow-up of simplification therapy with once-daily emtricitabine, didanosine and efavirenz in HIV-infected patients (ALIZE ANRS 099 trial).

BACKGROUND: once-daily combinations of efavirenz and two nucleoside analogues are recommended for the treatment of HIV infection. Long-term efficacy and safety data are scarce for the combination of efavirenz, emtricitabine and didanosine. METHODS: the ALIZE ANRS 099 trial enrolled 355 adults with plasma HIV RNA levels of <400 copies/mL under a protease inhibitor-based regimen, who were randomized to remain on this regimen or to switch to a once-daily regimen of emtricitabine, didanosine and efavirenz for 48 weeks. An extended 4 year follow-up was available for the 178 patients who switched to the efavirenz-containing regimen, and assessed plasma HIV RNA levels, CD4 cell counts, safety and tolerability. RESULTS: after a median follow-up of 42 months, 121 patients (68%) remained on an efavirenz-based regimen, and 62% and 57% had plasma HIV RNA levels of <400 and <50 copies/mL, respectively, in an intent-to-continue analysis with missing data and treatment discontinuation considered as failure. There was a significant increase in CD4 cell count of 41 cells/mm(3). Drug-related adverse events were the main reason for treatment discontinuation in 26 patients (15%), and 15 were reported during the first year of therapy (58%). There was no emergence of clinically defined lipodystrophy, and lipid and glucose profiles were favourable with a significant increase from baseline of high-density lipoprotein cholesterol levels (median increase 12 mg/dL, P < 10(-4)). CONCLUSIONS: a once-daily regimen of emtricitabine, didanosine and efavirenz provided a durable antiretroviral response and was well tolerated through 4 years of therapy.

Twelve-year experience of nevirapine use: benefits and convenience for long-term management in a French cohort of HIV-1-infected patients.

OBJECTIVE: To describe safety and long-term efficacy of nevirapine (NVP) in a real-life setting. RESULTS: From 1996 to 2008, among the 745 patients who received NVP, 592 were still followed in our center; of these, 231 had stopped NVP because of failure (42%), side effects (28%), other causes (30%). Twenty-seven percent of discontinuations occurred in the first 3 months; 68% were related to adverse events. In June 2008, 361/592 patients (61%) were still on NVP for a median duration of 176 weeks (range, 0.3-600), including 18% of naïve patients, 15% of patients who initiated NVP in the context of virologic failure, and 66% of patients with an undetectable viral load (switch strategy). Median CD4 cell count increased from 377/microL (range, 8-1449) to 549/microL (range, 144-1621). Viral load was below 200 copies/mL at the latest visit in 97%, 96%, and 100% of the patients in the naïve, failure, and switch groups, respectively. Over a 5-year period, the rate of antiretroviral drug persistence was 60.9% for NVP, 41.4% for efavirenz, and 23% for lopinavir/ritonavir (P < .0001). CONCLUSIONS: In a real-life setting, NVP demonstrates sustained efficacy and good safety and is very convenient to use as reflected by a high rate of persistency.

Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus.

Twelve heavily pretreated, perinatally infected adolescents in virological failure were treated with a combination of raltegravir, r-darunavir and etravirine, as part of an expanded access program in France. After a 12-month median follow-up, viral load was <400 copies/ml in 11 (<50 in six). No grade > 2 side effects were recorded. Additional data and marketing authorizations are awaited, but preliminary results in adolescents with extensive multidrug resistant virus are encouraging.

Disturbance of apolipoprotein B100 containing lipoprotein metabolism in severe hyperlipidemic and lipodystrophic HIV patients on combined antiretroviral therapy: evidences of insulin resistance effect.

The aim was to study the mechanisms involved in the dyslipidemia associated with lipodystrophy in HIV infected patients on antiretroviral therapy (ART). We investigated the in vivo kinetics of apolipoprotein B100 (apoB) containing lipoproteins using a 14 h primed constant infusion of [5,5,5, (2)H(3)] leucine and compartmental modelling in normolipidemic without lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy (7 patients, LD) treated with ART. Subjects in group LD showed higher plasma triglycerides (5.73+/-3.58 vs 1.29+/-0.54 g/L, p<0.005), total cholesterol (2.98+/-0.95 vs 1.74+/-0.26 g/L, p<0.05), apoB (1.49+/-1.11 vs 0.51+/-0.11 g/L, p<0.005) and apolipoprotein CIII in apoB containing lipoproteins (117.7+/-42.2 vs 22.6+/-23.9 g/L, p<0.005). LD subjects exhibited an insulin resistant as observed by higher HOMA (3.44+/-1.62 vs 1.60+/-0.61, p<0.05). They exhibited an increase in VLDL (1.24+/-0.33 vs 0.80+/-0.21 mg/kg/h, p<0.05), decrease in IDL (0.20+/-0.10 vs 0.48+/-0.24 mg/kg/h, p<0.05) and no difference in LDL (0.38+/-0.19 vs 0.45+/-0.25 mg/kg/h) production rate. LD subject also showed a dramatic decrease in transformation of VLDL to IDL (0.013+/-0.010 vs 0.258+/-0.206 h(-1), p<0.005) and IDL to LDL (0.088+/-0.093 vs 0.366+/-0.189 h(-1), p<0.05) and a decrease in fractional catabolic rate (FCR) of VLDL (0.199+/-0.132 vs 0.555+/-0.398 h(-1), p<0.05), IDL (0.110+/-0.08 vs 0.523+/-0.275 h(-1), p<0.05) and LDL (0.010+/-0.005 vs 0.025+/-0.014 h(-1), p<0.05). These disturbances, overproduction and an overall delayed catabolism of apoB, are similar to those observed using the same protocol in insulin resistant subjects. Our study suggests that metabolic disturbance of apoB100 observed in lipodystrophic HIV in combined antiretroviral therapy are consecutive to insulin resistance induced by the treatment.